The taxane family of terpenes has received much attention in the scientific and medical community, because members of this family have demonstrated broad spectrum of anti-leukemic and tumor-inhibitory activity. A well-known member of this family is paclitaxel (Taxol®).

Paclitaxel was first isolated from the bark of the pacific yew tree (Taxus brevifolia) in 1971, and has proved to be a potent natural anti-cancer agent. To date, paclitaxel has been found to have activity against different forms of leukemia and against solid tumors in the breast, ovary, brain, and lung in humans.
As will be appreciated, this beneficial activity has stimulated an intense research effort over recent years with a view to identifying other taxanes having similar or improved properties, and with a view to developing synthetic pathways for making these taxanes, such as paclitaxel.
This research effort led to the discovery of a synthetic analogue of paclitaxel, namely, docetaxel (also known as Taxotere®). As disclosed in U.S. Pat. No. 4,814,470, docetaxel has been found to have a very good anti-tumour activity and better bioavailability than paclitaxel. Docetaxel is similar in structure to paclitaxel, having t-butoxycarbonyl instead of benzoyl on the amino group at the 3′ position, and a hydroxy group instead of the acetoxy group at the C-10 position.

As will be appreciated, taxanes are structurally complicated molecules, and the development of commercially viable synthetic methods to make taxanes has been a challenge. A number of semi-synthetic pathways have been developed over the years, which typically begin with the isolation and purification of a naturally occurring starting material, which can be converted to a specific taxane derivative of interest. Cabazitaxel (I) is an anti-tumor drug which belongs to the taxol family. It differs from docetaxel in that it has methoxy groups at positions 7 and 10 of the molecule, as opposed to the hydroxyl groups at equivalent positions in docetaxel. Cabazitaxel is obtained by semi-synthesis from an extract of Chinese yew (Taxus mairei). It is understood that cabazitaxel can be obtained via semi-synthesis from other taxus species including T. candensis, T. baccatta, T. chinensis, T. mairei etc.

Cabazitaxel is a semi-synthetic derivative of the natural taxoid 10-deacetylbaccatin III (10-DAB) with potentially unique antineoplastic activity for a variety of tumors. Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation. This drug is a microtubule depolymerization inhibitor, which can penetrate blood brain barrier (BBB).
Cabazitaxel was recently approved by the US Federal Drug Administration (FDA) for the treatment of docetaxel resistant hormone refractory prostate cancer. It has been developed by Sanofi-Aventis under the trade name of Jevtana. The CAS number for the compound is 183133-96-2. A synonym is dimethoxydocetaxel. The compound is also known as RPR-116258A; XRP6258; TXD 258; and axoid XRP6258.
The free base form of cabazitaxel has the chemical name (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-9-(((2R,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-3-phenylpropanoyl)oxy)-11-hydroxy-4,6-dimethoxy-4-a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-yl benzoate.
In a first part of this description, taxel drugs including paclitaxel (taxol), docetaxel (taxotere) and cabazitaxel may be prepared starting from 10-deacetylbaccatin (known as 10-DAB) derived from Taxus plants, via semi-synthesis. Furthermore, the same inventive methodologies can be used to semi-synthesize cabazitaxel starting from 9-dihydro-13-acetylbaccatin III (9-DHB).
Patent numbers CN1213042C, CN152870, CN1179716 and CN1179775 disclose methods to prepare cabazitaxel from 10-DAB (herein compound II).

A typical prior art synthesis route is as follows:

The method above which synthesizes cabazitaxel has many synthetic steps, a very low overall yield and high price.
There is therefore a need in the art to develop new methods to synthesize cabazitaxel and its intermediates to improve the yield of cabazitaxel, simplify the methodology and optimize the synthetic technology.